Use of mirtazapine for treating sleep apneas

ABSTRACT

The compound mirtazapine is found to be effective in treating sleep apneas. Optionally, mirtazapine is combined with an SSRI such as fluoxetin.

The present invention pertains to the treatment of sleep apneas. Sleepapnea is defined as the cessation of breathing during sleep. Itcomprises a spectrum of respiration-related disorders with varyingseverity and morbidity, involving periods, during sleep, in whichairflow is disturbed. The usual classification of sleep apneasdistinguishes obstructive, central, and mixed apneas, depending on thepresence or absence of respiratory efforts during the periods in whichairflow has ceased. In the case of the obstructive sleep apnea syndrome,which is the most familiar apnea, sporadic recurring collapse of thepatient's upper airway occurs during sleep. If the collapse is complete,there is no air exchange at the nose and the mouth, and breathing isinterrupted. The usual result is a partial arousal from sleep, and areturn to normal breathing. The patient in most instances does not haveany knowledge or memory of these apnea episodes, but finds himselfconstantly suffering from fatigue and daytime sleepiness for no apparentreason. These recurrent apnea episodes with resultant hypoxemia andfragmented sleep can have serious neurologic and cardiac consequences.While the obstructive sleep apnea is a physical blockade, central sleepapnea is defined as a neurological disorder, causing cessation of allrespiratory effort during sleep, usually with decreases in blood oxygensaturation. The effects of both types of apneas are highly similar.Mixed apnea is a combination of the previous two. An episode of mixedsleep apnea usually starts with a central component and then becomesobstructive in nature.

The sleep apnea syndrome today is regarded as a serious problem, as itoccurs widely, and there is a true lack of an effective treatment.Surgical and mechanical interventions have been suggested and tried astreatments, as has oxygen administration during sleep, but none of theseare recognised to be very suitable. Pharmacological intervention hasalso been tried, but with little success. In fact, several kinds ofrespiratory stimulants, theophylline, antidepressants, and progestogenshave been used to treat sleep apneas, but none of these has been foundto be very effective.

It is an object of the present invention to provide an effectivemedicine against sleep apneas. To this end, the invention is a methodfor the treatment of an animal, for example, a mammal including a humanpatient, suffering from sleep apnea, comprising administering aneffective amount of mirtazapine. The invention also involves the use ofmirtazapine for the manufacture of a medicament for the treatment ofsleep apnea.

Without wishing to be bound by theory, the applicant, with the hindsightof the unexpected effect of the invention, believes that it is theparticular serotonergic profile of mirtazapine which is responsible forthe efficacy against sleep apnea.

It should be noted that in a 1992 scientific publication (The Journal ofPharmacology and Experimental Therapeutics, Vol. 260 No. 2, pages917-924), the pharmacological characterisation of the receptorsmediating 5-HT (serotonin)—induced apnea has been investigated bystudying the inhibitory effects of exogenous 5-HT on respiration andphrenic nerve activity in anaesthetised rats. This study supports thenowadays recognised potential importance of serotonin receptors inrespiration, and indicates, int.al., that 5-HT and 2methyl-5-HT provokedcentral apneas are antagonised by ondansetron (GR 38032 F), which is aselective 5HT₃ antagonist.

The invention resides in the finding that an effective medicine againstsleep apneas is provided on the basis of the compound mirtazapine. Thiscompound displays a combined serotonergic antagonistic activity to theeffect that it simultaneously is a combined 5HT2A, 5HT2C and 5HT3antagonist. The invention in general pertains to the use of thiscompound for manufacturing a medicament for treating sleep apneas,Surpisingly, the compound is not only useful as a therapy against sleepapneas of the central type, but also against sleep apneas of theobstructive and mixed types.

Mirtazapine is known, e.g. from U.S. Pat. No. 4,062,848. The compoundcontaining a centre of chirality, it may exist as different enantiomersand enantiomeric mixtures. The present invention includes the use of anyparticular enantiomer alone, or in a mixture with one or morestereoisomers, in any proportion including racemic mixtures. The presentinvention includes any salts of the compound, such as acid additionsalts, for example, hydrochloric, fumaric, maleic, citric or succinicacid, these acids being mentioned only by way of illustration andwithout implied limitation. These compounds can be prepared inaccordance with U.S. Pat. No. 4,062,848, incorporated herein byreference.

In a preferred embodiment, the aforementioned compound is combined witha selective serotonin reuptake inhibitor (SSRI). SSRI's, andpharmaceutically acceptable salts thereof, are known and have beenavailable since the early 1980s. They include zimelidine, fluoxetine andfluvoxamine. Other SSRI's are for example citalopram, cericlamine,femoxetine, ifoxetine, cyanodothiepin, sertraline, paroxetine, andlitoxetine. SSRI's are known to the skilled person, and may be preparedby any method known in the art. For example, fluoxetine orpharmaceutically acceptable salts thereof, can be prepared in accordancewith U.S. Pat. No. 4,314,081, incorporated herein by reference.

A further benefit of mirtazapine, is that it also has antidepressant andanxiolytic properties, which helps to overcome secondary symptoms ofwhich sleep apnea patients may suffer. Moreover mirtazapine improves thequality of sleep in general, which up to date has not been achieved withtreatments of sleep apnea.

The compounds used according to the invention are to be administered indosages of from 0.01 to 30 mg per kilogram body weight of the recipientper day, preferably in the range of 0.1 to 5 mg per kg body weight. Inmost instances, the preferred dosage of mirtazapine is 5 to 45 mg perday, and more preferably 15-30 mg. The SSRI dose may vary depending onthe potency and efficacy of the specific active substance, but willgenerally be in the range of from 5 to 300 mg per day. E.g. citalopramand paroxetine will have a suitable dose of 40-50 mg, while the dosesfor fluvoxamine and sertraline will be 200-300 mg per day. In general, asuitable dose of an SSRI or a pharmaceutically acceptable salt thereoffor administration to a human will be in the range of 0.01 to 50 mg perkilogram body weight of the recipient per day, preferably in the rangeof 0.1 to 3 mg per kilogram body weight per day. The preferred SSRI isfluoxetine which, administered in a dose within the range of 0.01 to 10mg per kilogram body weight of the recipient per day, preferably in therange of 0.1 to 1 mg per kilogram body weight per day, together with theabove preferred dose of mirtazapine forms the best choice for providinga highly effective medicament for the treatment of sleep apneas of theobstructive and mixed types.

The method of treatment of sleep apneas wherein the compounds accordingto the invention are administered for therapy to an animal e.g. a mammalincluding a human, may be carried out in conventional manner, using allkinds of methods, including parenteral, peroral or rectaladministration. Administration in the form or oral dosage units, such astablets or capsules, is preferred. In the method of the inventionaccording to which the aforementioned compounds are used formanufacturing a medicine, the compound can be mixed with all kinds ofpharmaceutically acceptable carriers, depending on the method ofadministration intended. For the preferred, peroral, method ofadministration, the active compound is taken up in known manner in acomposition from which granules or tablets are prepared.

The term “dosage unit” generally refers to physically discrete unitssuitable as unitary dosages for humans, each containing a predeterminedquantity of active material calculated to produce the desired effect,for instance tablets, pills, powders, suppositories, capsules and thelike.

Methods and compositions for making such dosage units are well-known tothose skilled in the art. For example, conventional techniques formaking tablets and pills, containing active ingredients, are describedin the standard reference, Gennaro et al., Remington's PharmaceuticalSciences, (18th ed., Mack Publishing Company, 1990, see especially Part8: Pharmaceutical Preparations and Their Manufacture). For making dosageunits, e.g. tablets, the use of conventional additives, e.g. fillers,colorants, polymeric binders and the like is contemplated. In generalany pharmaceutically acceptable additive which does not interfere withthe function of the active compounds can be used in the one or more ofthe compositions.

Suitable carriers with which the compositions can be administeredinclude lactose, starch, cellulose derivatives and the like used insuitable amounts. Lactose is a preferred carrier. Mixtures of carrierscan also be used.

The manufacture of the dosage units according to the invention caninvolve standard pharmaceutical methods known to the skilled personwithout further elucidation.

TEST EXAMPLE

The efficacy of the compounds according to the invention is tested bystudying the effects of administration of mirtazapine (in the range offrom 0.05 to 25 mg/kg) in adult Sprague-Dawley rats by monitoring sleep,respiration and blood pressure for a minimum of 6 hours. This follows anaccepted physiological animal model (ref. Monti et al.,Pharmacol.Biochem.Behav., 51:125-131;1995). The effective suppression bymirtazapine of sleep apneas in the rat model is indicative for similarefficacy in humans.

What is claimed is:
 1. A method for the treatment of sleep apneas in ananimal, comprising administering a therapeutically effective amount ofmirtazapine or a pharmaceutically acceptable salt thereof.
 2. The methodaccording to claim 1, further comprising administering a selectiveserotonin reuptake inhibitor (SSRI).
 3. The method according to claim 1,wherein the animal is a human.
 4. The method according to claim 1,wherein the SSRI is administered orally.
 5. A method for making amedicament for treating sleep apneas, comprising admixing mirtazapine ora pharmaceutically acceptable salt thereof with a pharmaceuticallyacceptable additive.
 6. The method of claim 5, further comprisingadmixing a selective serotonin reuptake inhibitor (SSRI) with saidpharmaceutically acceptable additive.
 7. The method of claim 5, whereinsaid medicament is a dosage unit for oral administration.